Sequence variants ofDLC1 in colorectal and ovarian tumours

Wilson, Peter J.; McGlinn, Edwina; Marsh, Anna; Evans, Timothy M.; Arnold, Jeremy M.; Wright, Kim; Biden, Kelli G.; Young, Joanne; Wainwright, Brandon J.; Wicking, Carol; Chenevix‐Trench, Georgia

doi:10.1002/(sici)1098-1004(200002)15:2<156::aid-humu4>3.0.co;2-4

Cited by 30 publications

(31 citation statements)

References 18 publications

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“…Thus, the usage of different transcription start sites would not affect the normal physiologic function of DLC1, or even the transcription efficiencies as shown by our semi-quantitative RT-PCR (Figure 1a). DLC1 also has multiple isoforms and alternative promoters (Wilson et al, 2000), and the present study focused on the transcript variant 2 (NM_006094). Further studies on DLC1 in tumorigenesis need to be carried out on its alternative splicing variants and promoter usages, their possibly different functions, and their genetic mutations.…”

Section: Discussionmentioning

confidence: 99%

The major 8p22 tumor suppressor DLC1 is frequently silenced by methylation in both endemic and sporadic nasopharyngeal, esophageal, and cervical carcinomas, and inhibits tumor cell colony formation

Seng¹,

Low²,

et al. 2006

Oncogene

125

118

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Identification of tumor suppressor genes (TSG) silenced by methylation uncovers mechanisms of tumorigenesis and identifies new epigenetic tumor markers for early cancer detection. Both nasopharyngeal carcinoma (NPC) and esophageal carcinoma are major tumors in Southern China and Southeast Asia. Through expression subtraction of NPC, we identified Deleted in Liver Cancer 1 (DLC1)/ARHGAP7 (NM_006094) -an 8p22 TSG as a major downregulated gene. Although expressed in all normal tissues, DLC1 was silenced or downregulated in 11/12 (91%) NPC, 6/15 (40%) esophageal, 5/8 (63%) cervical and 3/9 (33%) breast carcinoma cell lines. No genetic deletion of DLC1 was detected in NPC although a hemizygous deletion at 8p22-11 was found by 1-Mb array-CGH in some cell lines. We then located the functional DLC1 promoter by 5 0 -RACE and promoter activity assays. This promoter was frequently methylated in all downregulated cell lines and in a large collection of primary tumors including 89% (64/72) NPC (endemic and sporadic types), 51% (48/94) esophageal, 87% (7/8) cervical and 36% (5/14) breast carcinomas, but seldom in paired surgical marginal tissues and not in any normal epithelial tissue. The transcriptional silencing of DLC1 could be reversed by 5-aza-2 0 -deoxycytidine or genetic double knock-out of DNMT1 and DNMT3B. Furthermore, ectopic expression of DLC1 in NPC and esophageal carcinoma cells strongly inhibited their colony formation. We thus found frequent epigenetic silencing of DLC1 in NPC, esophageal and cervical carcinomas, and a high correlation of methylation with its downregulation, suggesting a predominant role of epigenetic inactivation. DLC1 appears to be a major TSG implicated in the pathogenesis of these tumors, and should be further tested as a molecular biomarker in patients with these cancers. Oncogene (2007) 26, 934-944.

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Section: Discussionmentioning

confidence: 99%

The major 8p22 tumor suppressor DLC1 is frequently silenced by methylation in both endemic and sporadic nasopharyngeal, esophageal, and cervical carcinomas, and inhibits tumor cell colony formation

Seng¹,

Low²,

et al. 2006

Oncogene

125

118

View full text Add to dashboard Cite

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“…To date, deletion of DLC-1 has been found in human liver and breast cancers, and aberrant DNA methylation of the promoter region has been observed in liver, breast, colon, prostate and gastric cancer cells in which DLC-1 gene expression is downregulated (Yuan et al, 1998(Yuan et al, , 2003aKim et al, 2003). Point mutation of the DLC-1 gene occurs only in a subset of different types of solid tumors and thus it appears not to be a major mechanism responsible for DLC-1 gene inactivation in NSCLCs or in other cancers (Wilson et al, 2000;Yin et al, 2002;Park et al, 2003;Zheng et al, 2003).…”

Section: Discussionmentioning

confidence: 99%

DLC-1 operates as a tumor suppressor gene in human non-small cell lung carcinomas

et al. 2003

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The deleted in liver cancer (DLC-1) gene at chromosome 8p21-22 is altered mainly by genomic deletion or aberrant promoter methylation in a large number of human cancers such as breast, liver, colon and prostate and is known to have an inhibitory effect on breast and liver tumor cell growth. Given the high frequency of deletion involving region 8p21-22 in human non-small cell lung carcinoma (NSCLC), we examined alterations of DLC-1 in a series of primary tumors and tumor cell lines and tested effects of DLC-1 on tumor cell growth. A significant decrease or absence of the DLC-1 mRNA expression was found in 95% of primary NSCLC (20/21) and 58% of NSCLC cell lines (11/19). Transcriptional silencing of DLC-1 was primarily associated with aberrant DNA methylation, rather than genomic deletion as 5-aza-2 0 -deoxycytidine induced reactivation of DLC-1 expression in 82% (9/11) NSCLC cell lines showing downregulated DLC-1. It was further evidenced by an aberrant DLC-1 promoter methylation pattern, which was detected by Southern blotting in 73% (8/11) of NSCLC cell lines with downregulation of the gene. The transfer of DLC-1 into three DLC-1 negative cell lines caused a significant inhibition in cell proliferation and/or a decrease in colony formation. Furthermore, stable transfer of DLC-1 abolished tumorigenicity in nude mice of two cell lines, suggesting that DLC-1 plays a role in NSCLC by acting as a bona fide new tumor suppressor gene.

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“…In tumors, dysregulation of the RhoGTPases-associated signaling pathways may lead to motile and invasive phenotype (Schmitz et al, 2000). Wilson et al (2000) detected one missense mutation of the DLC1 gene in a series of 126 colorectal and 33 ovarian tumors and cell lines. Ng et al (2000) detected homozygous deletion in two of six hepatocellular carcinomas and two hepatoma cell lines.…”

Section: Discussionmentioning

confidence: 99%

Identification of a region of homozygous deletion on 8p22–23.1 in medulloblastoma

Yin

Pang

2002

Oncogene

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To identify critical tumor suppressor loci that are associated with the development of medulloblastoma, we performed a comprehensive genome-wide allelotype analysis in a series of 12 medulloblastomas. Non-random allelic imbalances were identi®ed on chromosomes 7q (58.3%), 8p (66.7%), 16q (58.3%), 17p (58.3%) and 17q (66.7%). Comparative genomic hybridization analysis con®rmed that allelic imbalances on 8p, 16q and 17p were due to loss of genetic materials. Finer deletion mapping in an expanded series of 23 medulloblastomas localized the common deletion region on 8p to an interval of 18.14 cM on 8p22 ± 23.2. We then searched within the region of loss on 8p for loci that might contain homozygous deletion using comparative duplex PCR. An overlapping homozygous deletion region was identi®ed in a 1.8 cM interval on 8p22 ± 23.1, between markers D8S520 and D8S1130, in two medulloblastomas. This region of homozygous deletion also encompasses the 1.4 cM minimal deletion region detected on 8p in ductal carcinoma in situ of breast. In conclusion, we reported for the ®rst time a detailed deletion mapping on 8p in medulloblastoma and have identi®ed a region of homozygous deletion on 8p22 ± 23.1 that is likely to contain a critical tumor suppressor gene involved in the development of medulloblastoma.

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Sequence variants ofDLC1 in colorectal and ovarian tumours

Cited by 30 publications

References 18 publications

The major 8p22 tumor suppressor DLC1 is frequently silenced by methylation in both endemic and sporadic nasopharyngeal, esophageal, and cervical carcinomas, and inhibits tumor cell colony formation

The major 8p22 tumor suppressor DLC1 is frequently silenced by methylation in both endemic and sporadic nasopharyngeal, esophageal, and cervical carcinomas, and inhibits tumor cell colony formation

DLC-1 operates as a tumor suppressor gene in human non-small cell lung carcinomas

Identification of a region of homozygous deletion on 8p22–23.1 in medulloblastoma

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